Rheumatoid arthritis (RA), which is affecting approximately 0.5-1.0% of the adult population worldwide and more than 2 million people in the United States, is a chronic debilitating disease of the joints characterized by leukocyte infiltration, hyper-proliferation of synovial cells and bone destruction. The hyper-proliferation of synovial tissues, which results in increased production of synovial proinflammatory cytokines and direct invasions and destruction of the bone and cartilage, is essential to RA development. We found in our preliminary study that Synoviolin (SYVN1) functions as a key player in synovial fibroblasts proliferation and apoptosis. The expression of SYVN1 is highly associated with arthritis development in DBA1 mice. Over-expression of SYVN1 induces growth of mice synovial fibroblasts and inhibits ER stress-mediated apoptosis. At the molecular level, we found that SYVN1 down-regulates proapoptotic factor IRE1 and CHOP. Interestingly, SYVN1 induces ubiquitination and degradation of IRE1, suggesting SYVN1 inhibits the proapoptotic functions of IRE1 via ubiquitination-mediate protein degradation. The C-terminus of SYVN1 (SYVN1-C) is required for this E3 ligase to specifically recruit its substrate IRE1 for ubiquitination. Genetically deletion of SYVN1-C expression in mice caused increased IRE1 protein levels in their synovial cells. In this application, we plan to further delineate the physiological functions of SYVN1-mediated ubiquitination in the overgrowth of synovial cells both in vitro and in vivo using newly generated SYVN1-C knock-out mice. Therefore, the proposed researches are to address two specific aims: 1) To illuminate the molecular mechanisms of SYVN1-mediated protein ubiquitination in regulating the apoptosis of synovial cells; 2) To determine SYVN1-mediated IRE1 ubiquitination in the development of collagen-induced arthritis (CIA) using SYVN1-C-/- mice. PUBLIC HEALTH RELEVANCE. The results from our proposed research will lead to a better understanding the molecular mechanisms of arthritis development. The SYVN1/IRE1 signaling pathway can be potentially targeted for the treatment of rheumatoid arthritis. Generation of SYVN1-C-/- mice will provide a unique mouse model in arthritis research.